The antigen binding specificity of all antibodies is determined by the selection of a single variable (VH and VL), joining (JH and VL), and diversity (DH only) gene segments which recombine to generate their genetic codes. Different combinations of gene segments can result in the same V gene segment contributing to the codes for very different antigen-binding specificities. Even though there may be only about 80 VH genes in humans, they are not all expressed with equal frequency. Certain VH gene segments have been observed to occur frequently among plasmacytomas in mice, and one particular VH subgroup (VHIII) is disproportionately expressed in rheumatoid factor (RF) antibodies in humans. Therefore, it seems likely that one level at which RF synthesis is controlled may be in VH gene segment selection. We propose to study this hypothesis by determining which, if any, VH genes selectively encode RF antibodies. Another level at which antigenic specificity of antibodies is influenced is in the somatic mutation of the rearranged VDJ gene exon. It is possible that aberrant mutational processes might allow RF-synthesizing cells to escape the regulation of immune suppression. We will test this hypothesis by comparing the cDNA sequences of several RF isolates with that of their unrearranged germline counterparts. In addition, the large local rheumatoid arthritis patient population long with the availability of several well-studied multiplex families will allow us to study VH gene polymorphisms that correlate with in vivo RF production and HLA haplotypes. The proposed studies will permit us to examine at the molecular genetic level a potentially important variable in autoimmune disease susceptibility.